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\begin{document}

\title{Pallister-Hall syndrome diagnosed in a young man after an acute adrenal
crisis}



\author[1]{Anis Grassa}%
\author[1]{Meriem Yazidi}%
\author[1]{Jihene Marrakchi}%
\author[1]{Chaima Bel Hadj Sliman}%
\author[1]{Ibtissem Oueslati}%
\author[1]{Melika Chihaoui}%
\affil[1]{La Rabta University Hospital Center}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Pallister-Hall syndrome is a very rare genetic disorder. The diagnosis
is usually suspected at the young age when a hypothalamic hamartoma is
associated with polydactyly. We report the case of an 18-year-old man in
whom the diagnosis of PHS was made during his hospitalization for acute
adrenal insufficiency.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Pallister-Hall syndrome (PHS) is a very rare congenital syndrome, and
its exact prevalence is still unknown
(\textless{}1/10\textsuperscript{6}). It was first described in 1981 by
Philip Pallister and Judith Hall. To date only 100 patients have been
described worldwide {[}1{]}. The genetic abnormalities involved are
mutations in the GLI3 gene (7p13) encoding a transcription factor
activated by the Sonic hedgehog signalling pathway {[}2-4{]}. The
clinical diagnosis is usually made when a hypothalamic hamartoma is
associated with polydactyly {[}5,6{]}. Additional symptoms and findings
may include oro-facial malformations and other abnormalities like
genitourinary malformations {[}7,8{]}. Endocrine manifestations are
mostly related to hypothalamic hamartoma. They consist of
hypopituitarism, which can affect one or more pituitary axes, and
precocious puberty {[}8{]}. Here, we report the case of an 18-year-old
young man in whom the diagnosis of PHS was delayed until his
hospitalization in the endocrinology department for acute adrenal
insufficiency.

\textbf{Case presentation}

The patient was an 18 years old young man who presented to the emergency
room with clinical and biological features of an adrenal crisis. The
clinical course was good after intravenous hydrocortisone replacement
and infusion with physiological saline solution. The medical history
revealed several surgeries: a corrective one for meso-axial polydactyly,
a surgery for testicular ectopia and for a hypothalamic tumour diagnosed
at the age of three years complicated with hypopituitarism. He would
have received growth hormone for two years from the age of twelve. He
was on hormone replacement therapy for hypothyroidism and adrenal
insufficiency, and he stopped his treatment for a week. He had no
medical follow-up for several years. The patient's family history was
unknown as he was an adopted child.

Physical examination showed a height of 157 cm (-3SD), a weight of 68 kg
and a BMI of 27.5 kg /m\selectlanguage{ngerman}². We noted a surgically corrected postaxial
polydactyly and an inequality of the two lower limbs (fig 1).
Examination of the external genitalia revealed a micropenis and
hypoplastic testes (fig 2). PHS was suspected and further investigations
were then performed. An otolaryngology examination showed a bifid
epiglottis as well as a laryngeal cleft (fig 3). X-rays of the left hand
revealed a surgically corrected postaxial type A polydactyly (fig 4A).
Pelvic x-ray showed bone demineralisation and the Risser stage was 4
(fig 4B). Ultrasounds of the heart, the abdomen and kidneys were normal.
The pelvic ultrasound showed hypoplastic testes. Brain MRI revealed a
sellar and suprasellar mass measuring 28x25x24 mm corresponding to a
hypothalamic hamartoma (fig 5). On biochemical evaluation, the renal and
hepatic functions, blood count, serum calcium and serum phosphorus
results were normal. The pituitary assessment showed a thyrotropin and
gonadotropin deficiencies (Table 1).

\textbf{Discussion:}

The diagnosis of PHS is usually suspected at a young age based on the
association of polydactyly and hypothalamic hamartoma {[}1,5-9{]}.
However, due to its extreme rarity\emph{,} the diagnosis may be
unrecognized for a long time. Endocrine manifestations can then be in
the foreground and reveal the diagnosis as was the case for our patient
who presented with an adrenal crisis. Adrenal insufficiency is in most
cases linked to a hypothalamic hamartoma which is noted in 90 to 100\%
of cases of PHS {[}4,9{]}. Cases of congenital adrenal hypoplasia have
also been reported {[}8,9{]}. J G Hall's review reports two PHS cases of
death at birth secondary to adrenal insufficiency {[}10{]}. Hypothalamic
hamartoma leads to one or more pituitary axes deficiencies. However,
corticotropin deficiency seems rare in this syndrome, especially in
familial forms {[}8{]}. Growth hormone deficiency appears to be the most
common pituitary deficiency, but short stature in PHS may also be the
result of intrauterine growth retardation {[}9{]}. Panhypopituitarism
has only been reported in one case {[}9{]}. For our patient, it is not
clear if pituitary deficiencies were secondary to the hamartoma or to
the hypothalamic-pituitary surgery.

It should also be noted that the characteristics of hamartoma in PHS
differ from those of non-syndromic hamartomas. Epilepsy, behavioral
disturbances and gelastic seizures are less common in PHS and respond
better to treatment if they are present {[}8, 11,12{]}. Our patient had
no history of seizures and had no behavioral disturbances. Precocious
puberty can also reveal hamartoma. Its prevalence seems to be less
important in hamartomas associated with PHS than in non-syndromic
hamartomas {[}11{]}. Asymptomatic hamartoma detected incidentally on
imaging have also been reported {[}13{]}. Thus, hamartomas in PHS
usually only require monitoring and surgery is usually not indicated.

The diagnosis of PHS requires screening for associated abnormalities. A
bifid epiglottis was found on the otolaryngology examination of our
patient. This malformation is present in 40 to 100\% of cases in PHS and
is most often asymptomatic {[}8,9,13-15{]}. However, some patients
present with more severe posterior laryngeal clefts, leading to
potentially fatal respiratory failure {[}1,8{]}. Bifid epiglottis is a
rarely isolated birth defect, and its detection should suggest the
diagnosis of PHS {[}14{]}. Heart, lung, and kidney malformations have
also been reported in PHS. Cardiac, abdominal, and renal ultrasound were
normal in our patient. Urogenital abnormalities are reported in almost
half of cases such as micropenis, hypospadias and uterovaginal aplasia
{[}4, 9{]}. The micropenis in the present case can be related to the
syndrome but can also be explained by congenital hypogonadotropic
hypogonadism.

The management in the present case will be limited to hormonal
replacement therapy. The delay in the diagnosis and management of growth
hormone deficiency has compromised the final height of the patient. An
early treatment with growth hormone may have given him normal growth.
Galasso \emph{et al} . described a case of a PHS boy treated from the
age of 3 years and for 7 years with growth hormone. His final height was
5.5 cm above his target height {[}16{]}.

\textbf{Conclusion}

This patient's presentation shows that PHS may be misdiagnosed given its
extremely low prevalence. This syndrome can be revealed by an acute
adrenal crisis. Practitioners who may see patients with PHS at the young
age (pediatricians, surgeons) should be familiar with this disease to
avoid late diagnosis which may compromise patient prognosis.

\textbf{Ethical approval and consent to participate}

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy

\textbf{Conflict of interest}

There are no conflicts of interest.

\textbf{Acknowledgements}

The author thanks the patient for accepting the publication of the case

\textbf{References}

\begin{enumerate}
\tightlist
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